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WO2025136798A1 - Procédé de préparation de (s)-1-((s)-2-amino-3-(4-méthoxyphényl)propanoyl)-n-(4-(hydroxyméthyl)phénéthyl)-2-méthylpyrrolidine-2-carboxamide et de ses intermédiaires - Google Patents

Procédé de préparation de (s)-1-((s)-2-amino-3-(4-méthoxyphényl)propanoyl)-n-(4-(hydroxyméthyl)phénéthyl)-2-méthylpyrrolidine-2-carboxamide et de ses intermédiaires Download PDF

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Publication number
WO2025136798A1
WO2025136798A1 PCT/US2024/059924 US2024059924W WO2025136798A1 WO 2025136798 A1 WO2025136798 A1 WO 2025136798A1 US 2024059924 W US2024059924 W US 2024059924W WO 2025136798 A1 WO2025136798 A1 WO 2025136798A1
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formula
compound
salt
hydrate
solvate
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Inventor
Kevin M. Belyk
Zhiwei Chen
Stephen M. Dalby
Alan M. HYDE
Joshua Lee
Quihan LI
David A. Thaisrivongs
Jacob Henry WALDMAN
Tao Wang
Mark Weisel
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Merck Sharp and Dohme LLC
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Merck Sharp and Dohme LLC
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C213/02—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions involving the formation of amino groups from compounds containing hydroxy groups or etherified or esterified hydroxy groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups

Definitions

  • the present disclosure relates to a process for preparing (S)-1-((S)-2-amino-3-(4- methoxyphenyl)propanoyl)-N-(4-(hydroxymethyl)phenethyl)-2-methylpyrrolidine-2- carboxamide and its intermediates.
  • BACKGROUND [0003] Peptides are ubiquitous in nature and are fundamental components of pharmaceutically active compounds; however, the practicality and economics of their chemical synthesis on manufacturing scale present significant challenges.
  • the present disclosure is directed to a process for preparing a compound of Formula (X): H 2 N , or a salt, hydrate, or solvate thereof.
  • the synthesis comprises the steps of reacting compounds of Formulae (V), (VI), and (VIII): or salts, first intermediate.
  • FIG.1 is an X-ray powder diffraction pattern of a crystalline form of a hemi-sulfuric acid salt of the compound of Formula (X). The graph plots the intensity of the peaks as defined by counts per second versus the diffraction angle 2 theta (2 ⁇ ) in degrees.
  • FIG.2 is an X-ray powder diffraction pattern of a crystalline form of a hydrochloric acid salt of the compound of Formula (X).
  • the graph plots the intensity of the peaks as defined by counts per second versus the diffraction angle 2 theta (2 ⁇ ) in degrees.
  • DETAILED DESCRIPTION [0008] The present disclosure pertains to a method to synthesize the compound of Formula (X) from readily available commercial starting materials. The synthesis of the compound of Formula (X) poses additional selectivity challenges due to the primary alcohol group, which may also react with electrophiles competitively to the desired amine group. [0009] The present disclosure solves the shortcomings of the prior art via judicious choice of coupling conditions and employing a traceless, in situ masking strategy, which enables the highly regioselective coupling of the three building blocks without the need for additional protecting groups, maximizing process efficiency.
  • the present disclosure entails a carefully designed reaction sequence that enables the direct and selective amide coupling of the compound of Formula (V), the compound of Formula (VI), and the compound of Formula (VIII). Subsequently, deprotection and crystallization steps yield the compound of Formula (X) as a crystalline salt. This process not only exhibits remarkable efficiency but also demonstrates a high level of regioselectivity, ensuring the desired products are obtained with minimal unwanted side reactions.
  • the disclosed method is versatile and compatible with a wide range of substrates containing unprotected nucleophiles such as alcohols and amines. Advantageously, this versatility expands its applicability to various derivatives and bioactive molecules.
  • the present disclosure introduces a technological method for selective amide coupling to produce short peptide derivatives, removing the necessity for protecting groups and propelling the field of peptide synthesis forward.
  • the disclosed approach provides a more efficient, cost-effective, and versatile solution for the industrial-scale manufacturing of these biologically important molecules.
  • the present disclosure is directed to a novel, scalable synthesis of a compound of Formula (X): H 2 N , and or a pharmaceutically
  • the synthesis comprises the steps of reacting compounds of Formulae (V), (VI), and (VIII): OH HN BocHN Me or salts, first [0013]
  • the first intermediate is a compound of Formula (IX): BocHN or a pharmaceutically 25887
  • the instant process further comprises coupling the compounds of Formulae (V) and (VI) or the pharmaceutically acceptable salts, hydrates, or solvates thereof.
  • the crystalline salt is a hydrochloric acid salt.
  • the process further comprises the step of crystallizing the deprotected first intermediate to provide a hydrate or solvate of the crystalline salt of compound of Formula (X).
  • the process produces a hydrate of a crystalline hemi- sulfuric acid salt of a compound of Formula (X).
  • the process produces a solvate of a crystalline hemi-sulfuric acid salt of a compound of Formula (X).
  • the process produces a hydrate of a crystalline hydrochloric acid salt of a compound of Formula (X).
  • the process produces a solvate of a crystalline hydrochloric acid salt of a compound of Formula (X).
  • the compound of Formula (V) or the pharmaceutically acceptable salt, hydrate, or solvate thereof is prepared by deformylating a compound of Formula (IV): OH O or a pharmaceutically acceptable
  • the pharmaceutically acceptable salt, hydrate, or solvate thereof is prepared by reducing a compound of Formula (III): or a pharmaceutically
  • the compound of Formula (III) or the pharmaceutically acceptable salt, hydrate, or solvate thereof is prepared by reacting a compound of Formula (I): O or a pharmaceutically acceptable with a compound of Formula (II): O or a pharmaceutically acceptable salt, thereof.
  • the present disclosure is also directed to a compound of Formula (X) or a pharmaceutically acceptable salt, hydrate, or solvate thereof.
  • the present disclosure is directed to a crystalline form of the compound (S)-1-((S)-2-amino-3-(4-methoxyphenyl)propanoyl)-N-(4- (hydroxymethyl)phenethyl)-2-methylpyrrolidine-2-carboxamide.
  • the present disclosure is directed to a hemi-solvate crystalline form of the compound (S)-1-((S)-2-amino-3- (4-methoxyphenyl)propanoyl)-N-(4-(hydroxymethyl)phenethyl)-2-methylpyrrolidine-2- carboxamide. In an embodiment, the present disclosure is directed to a solvate crystalline form of the compound (S)-1-((S)-2-amino-3-(4-methoxyphenyl)propanoyl)-N-(4- (hydroxymethyl)phenethyl)-2-methylpyrrolidine-2-carboxamide.
  • the present disclosure is directed to an isolated crystalline form of the compound (S)-1-((S)-2-amino-3-(4-methoxyphenyl)propanoyl)-N-(4- (hydroxymethyl)phenethyl)-2-methylpyrrolidine-2-carboxamide.
  • the present disclosure is directed to an isolated hemi-solvate crystalline form of the compound (S)-1-((S)-2- amino-3-(4-methoxyphenyl)propanoyl)-N-(4-(hydroxymethyl)phenethyl)-2-methylpyrrolidine-2- carboxamide.
  • the present disclosure is directed to an isolated solvate crystalline form of the compound (S)-1-((S)-2-amino-3-(4-methoxyphenyl)propanoyl)-N-(4- (hydroxymethyl)phenethyl)-2-methylpyrrolidine-2-carboxamide.
  • the present disclosure is directed to an anhydrous crystalline form of the compound (S)-1-((S)-2-amino-3-(4-methoxyphenyl)propanoyl)-N-(4- (hydroxymethyl)phenethyl)-2-methylpyrrolidine-2-carboxamide.
  • the present disclosure is directed to an anhydrous hemi-solvate crystalline form of the compound (S)-1-((S)- 2-amino-3-(4-methoxyphenyl)propanoyl)-N-(4-(hydroxymethyl)phenethyl)-2-methylpyrrolidine- 2-carboxamide.
  • the present disclosure is directed to an anhydrous solvate crystalline form of the compound (S)-1-((S)-2-amino-3-(4-methoxyphenyl)propanoyl)-N-(4- (hydroxymethyl)phenethyl)-2-methylpyrrolidine-2-carboxamide.
  • the crystalline form of a hemi-sulfuric acid salt of the compound of Formula (X) is characterized by an X-ray powder diffraction pattern having peaks, expressed in degrees-2-theta at angles of ( ⁇ 0.2o) measured using CuK ⁇ radiation, selected from the group consisting of about 5.50 and 19.27_° 2 ⁇ .
  • the crystalline form of a hemi-sulfuric acid salt of the compound of Formula (X) is characterized by an X-ray powder diffraction pattern having peaks, expressed in degrees-2-theta at angles of ( ⁇ 0.2o) measured using CuK ⁇ radiation, selected from the group consisting of about 5.50, 7.72, 8.65, 9.41, 10.16, 10.93, 11.01, 12.19, 13.88, 14.40, 14.96, 15.41, 16.00, 16.38, 17.34, 17.63, 17.77, 18.13, 18.60, 19.27, 19.47, 19.69, 20.39, 21.13, 21.62, 22.18, 22.62, 23.42, 24.38, 24.75, 25.02, 25.91, 26.20, 27.42, 28.71, 28.99, 29.30, 29.55, 30.23, 31.35, 32.51, 32.78, 33.42, 34.56 ° 2 ⁇ .
  • the crystalline hemi-sulfuric acid salt form of the compound of Formula (X) is characterized by an X-ray powder diffraction pattern having peaks shown in Table 1 (expressed in degrees-2-theta at angles ⁇ 0.2o).
  • the X-ray powder diffraction pattern of a crystalline form of a hydrochloric acid salt of the compound of Formula (X) has an X-ray diffraction pattern substantially similar to that set forth in FIG.2.
  • the X-ray powder of the crystalline form of a hydrochloric acid salt of the compound of Formula (X) is characterized by an X-ray powder diffraction pattern having peaks, expressed in degrees-2-theta at angles of ( ⁇ 0.2o) measured using CuK ⁇ radiation, selected from the group consisting of about 6.71 and 13.17° 2 ⁇ .
  • the X-ray powder of the crystalline form of a hydrochloric acid salt of the compound of Formula (X) is characterized by an X-ray powder diffraction pattern having peaks, expressed in degrees-2-theta at angles of ( ⁇ 0.2o) measured using CuK ⁇ radiation, selected from the group consisting of about 6.71, 13.17, 16.30, and 19.16° 2 ⁇ .
  • the X-ray powder of the crystalline form of a hydrochloric acid salt of the compound of Formula (X) is characterized by an X-ray powder diffraction pattern having peaks, expressed in degrees-2-theta at angles of ( ⁇ 0.2o) measured using CuK ⁇ radiation, selected from the group consisting of of about 6.71, 12.90, 13.37, 14.01, 15.65, 16.10, 16.30, 17.49, 17.96, 18.60, 19.16, 19.71, 20.10, 21.01, 22.01, 22.65, 23.42, 24.61, 24.88, 26.18, 35.11 ° 2 ⁇ .
  • the crystalline form of a hydrochloric acid salt of the compound of Formula (X) is characterized by an X-ray powder diffraction pattern having peaks shown in Table 2 (expressed in degrees-2-theta at angles ⁇ 0.2o).
  • the synthesis of a compound of Formula (V) commences with condensation of 4-bromobenzaldehyde (Formula (I)) with N-vinyl formamide (Formula (II)).
  • the reaction can be mediated by a palladium catalyst to form an enamide (Formula (III)).
  • the reaction can involve a base.
  • the reaction can involve a solvent.
  • the reaction can involve other necessary reagents.
  • the enamide can be isolated as a crystalline solid.
  • the crystalline solid can be obtained via seeding or in the absence of seeding.
  • O O O H H O H limiting examples of solvents used in the synthesis of the compound of Formula (III) include EtOAc, DMF, THF, IPAc, PhMe, and DME.
  • Non-limiting examples of bases used in the synthesis of the compound of Formula (III) include DIPEA, triethylamine, tripropylamine, tri-n- butylamine, and tri-n-octylamine.
  • reagents used in the synthesis of the compound of Formula (III) include t-Bu3P-HBF4 and n-Bu4NBr.
  • the synthesis of the compound of Formula (III) is carried out at a temperature ranging from about 50 oC to about 100 oC, from about 60 oC to about 90 oC, from about 70 oC to about 80 oC, or from about 70 oC to about 75 oC. In an embodiment, the synthesis of the compound of Formula (III) is carried out at a temperature of about 73 oC.
  • reaction can involve a solvent.
  • reaction can involve other necessary reagents.
  • the reduction reaction can be a single or a double reduction reaction.
  • compound of Formula (IV) include Pd/C and Pd(OH) 2 /C.
  • solvents used in the synthesis of the compound of Formula (IV) include water, 1-PrOH, methanol, isopropanol, and n-butanol.
  • reagents used in the synthesis of the compound of Formula (IV) include triethylamine and hydrogen gas.
  • the synthesis of the compound of Formula (IV) is carried out at a temperature ranging from about 10 oC to about 70 oC, from about 20 oC to about 60 oC, from about 30 oC to about 50 oC, or from about 35 oC to about 45 oC. In an embodiment, the synthesis of the compound of Formula (IV) is carried out at a temperature of about 40 oC.
  • the formamide (Formula (IV)) undergoes acid-mediated deformylation to provide a crystalline Phe salt (Formula (V)), which is isolated directly by filtration.
  • the reaction can involve a solvent.
  • the crystalline Phe salt can exist as a hydrochloric acid salt.
  • the crystalline Phe salt can be obtained via seeding or in the absence of seeding.
  • OH OH NH 2 [0039]
  • the two- step process for synthesizing Formula (V) from Formula (III) is more concise and avoids the use of hazardous reagents such as lithium aluminum hydride, cyanide, and nitromethane.
  • Non-limiting examples of the deformylating agent used in the synthesis of the compound of Formula (V) include PivCl, NaOH, HCl, and methanesulfonic acid.
  • Non-limiting examples of the solvent used in the synthesis of the compound of Formula (V) include 1-PrOH, methanol, isopropanol, and n-butanol.
  • the synthesis of the compound of Formula (V) is carried out at a temperature ranging from about 10 oC to about 90 oC, from about 20 oC to about 80 oC, from about 30 oC to about 70 oC, from about 40 oC to about 60 oC, or from about 45 oC to about 55 oC.
  • the synthesis of the compound of Formula (V) is carried out at a temperature of about 50 oC.
  • Amide coupling of Formula (V) with amino acid MePro is achieved via an N-carboxyanhydride intermediate, formed through condensation of MePro with CDI (used as a coupling agent).
  • the reaction can involve a base.
  • the reaction can involve a solvent.
  • the MePro can exist as a hydrochloric acid solvate salt. HN OH Me
  • An CDI to give an N- is not isolated, but reacted further with the compound of Formula (V) to give the compound of Formula (VII).
  • this method avoids the need for protecting groups to couple the free amino acid selectively with the ambident nucleophile Phe (Formula (V)) with >99:1 selectivity.
  • the MePro-Phe intermediate (Formula (VII)) is then crystallized and isolated by filtration.
  • the MePro-Phe intermediate can exist as a hydrochloric acid salt.
  • the crystalline MePro-Phe intermediate can be obtained via seeding or in the absence of seeding.
  • Non-limiting examples of the coupling agent used in the synthesis of the compound of Formula (VII) include CDI and DSC.
  • Non-limiting examples of the solvent used in the synthesis of the compound of Formula (VII) include AcCl, IPA, DMF, NMP, MeCN, THF, and IPAc.
  • Non-limiting examples of the base used in the synthesis of the compound of Formula (VII) include DIPEA and TEA.
  • the synthesis of the compound of Formula (VII) is carried out at a temperature ranging from about -30 oC to about 50 oC, from about -20 oC to about 40 oC, from about -10 oC to about 30 oC, from about -5 oC to about 25 oC, or from about 0 oC to about 20 oC.
  • Coupling of the monomer Boc-MeTyr (Formula (VIII)) to MePro-Phe (Formula (VII)) is achieved through EDC-mediated amide coupling, which results in the protected Formula (IX).
  • the reaction can involve a nucleophilic additive.
  • the reaction can involve a base.
  • the reaction can involve a solvent.
  • HN BocHN of chloride Non-limiting examples of the nucleophilic additive used in the synthesis of the compound of Formula (IX) include HOPO and Oxyma.
  • Non-limiting examples of the solvent used in the synthesis of the compound of Formula (IX) include BSA, MTBE, DMF, DMAc, and MeCN.
  • Non-limiting examples of the base used in the synthesis of the compound of Formula (IX) include DIPEA and TEA.
  • the synthesis of the compound of Formula (IX) is carried out at a temperature ranging from about 0 oC to about 70 oC, from about 10 oC to about 60 oC, from about 20 oC to about 50 25887 oC, or from about 30 oC to about 40 oC. In an embodiment, the synthesis of the compound of Formula (IX) is carried out at a temperature of about 35 oC.
  • the crude stream is then treated with deprotecting agents to provide Formula (X).
  • deprotecting agents include methansulfonic acid and iso-butyryl chloride.
  • methanesulfonic acid is used to achieve deprotection and provide Formula (X), which is then crystallized and isolated to provide the corresponding sulfuric acid salt or hemi- sulfuric acid salt.
  • the reaction can involve other types of acids.
  • the reaction can involve a solvent.
  • the crystalline sulfuric acid salt or crystalline hemi-sulfuric acid salt can further exist as a hydrate form.
  • iso-butyryl chloride is used to achieve deprotection and provide Formula (X), which is then crystallized and isolated to provide the corresponding hydrochloric acid salt.
  • the crystalline hydrochloric acid salt can further exist as a 2-BuOH solvate or a 2- BuOH hemi-solvate form.
  • Other crystalline salts of Formula (X) include but are not limited to hydrochloride, hydrobromide, tosylate, edisylate, D-tartrate and oxalate salts.
  • the crystalline salts of Formula (X) can be obtained via seeding or in the absence of seeding.
  • Formula (X) of the acid used in the synthesis of the compound of Formula (X) include HCl, H 2 SO 4 , MsOH, and (iso- butyryl chloride + 2-BuOH).
  • the synthesis of the compound of Formula (X) is carried out at a temperature ranging from about 0 oC to about 90 oC, from about 10 oC to about 80 oC, from about 20 oC to about 70 oC, from about 30 oC to about 60 oC, from about 40 oC to about 50 oC, or from about 45 oC to about 50 oC.
  • the synthesis of the compound of Formula (IX) is carried out at a temperature of about 45 oC or about 50 oC.
  • All of the steps of the above processes are optionally but preferably conducted with agitation (e.g., stirring).
  • agitation e.g., stirring.
  • An example synthesis scheme of Formula (X) is shown in the following. 25887 Step 1 Heck Step 2a - Reduction t- P- O BocHN BocHN HN 0 .5
  • the term “comprising” may include the embodiments “consisting of” and “consisting essentially of.”
  • the terms “comprise(s),” “include(s),” “having,” “has,” “may,” “contain(s),” and variants thereof, as used herein, are intended to be open-ended transitional phrases, terms, or words that require the presence of the named ingredients/steps and permit the presence of other ingredients/steps.
  • compositions or processes may contain one or more asymmetric centers and can thus occur as “stereoisomers” including racemates and racemic mixtures, enantiomeric mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. Additional asymmetric centers may be present depending upon the nature of the various substituents on the molecule.
  • stereoisomer includes both enantiomers and mixtures of enantiomers, such as the specific 50:50 mixture referred to as a racemic mixture.
  • the independent syntheses of these diastereomers or their chromatographic separations may be achieved as known in the art by appropriate modification of the methodology disclosed 25887 herein.
  • Their absolute stereochemistry may be determined by the x-ray crystallography of crystalline products or crystalline intermediates which are derivatized, if necessary, with a reagent containing an asymmetric center of known absolute configuration. If desired, racemic mixtures of the compounds may be separated so that the individual enantiomers are isolated.
  • the separation can be carried out by methods well known in the art, such as the coupling of a racemic mixture of compounds to an enantiomerically pure compound to form a diastereomeric mixture, followed by separation of the individual diastereomers by standard methods, such as fractional crystallization or chromatography.
  • the coupling reaction is often the formation of salts using an enantiomerically pure acid or base.
  • the diasteromeric derivatives may then be converted to the pure enantiomers by cleavage of the added chiral residue.
  • the racemic mixture of the compounds can also be separated directly by chromatographic methods utilizing chiral stationary phases, which methods are well known in the art.
  • any enantiomer of a compound may be obtained by stereoselective synthesis using optically pure starting materials or reagents of known configuration by methods well known in the art.
  • the compounds of the present disclosure which contain olefinic double bounds, unless specified otherwise, are meant to include both E and Z geometric isomers.
  • Some of the compounds described herein may exist as tautomers which have different points of attachment of hydrogen accompanied by one or more double bond shifts.
  • a ketone and its enol form are keto-enol tautomers.
  • the individual tautomers as well as mixtures thereof are encompassed by the compounds of the present disclosure.
  • Some of the compounds described herein may exist as atropisomers when the rotational energy barrier around a single bond is sufficiently high to prevent free rotation at a given temperature, thus allowing isolation of individual conformers with distinct properties.
  • the individual atropisomers as well as mixtures thereof are encompassed by the compounds of the present disclosure.
  • individual atropisomers can be designated by established conventions such as those specified by the International Union of Pure Applied Chemistry (IUPAC) 2013 Recommendations.
  • the atoms may exhibit their natural isotopic abundances, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature.
  • the present disclosure as described and claimed herein is meant to include all suitable isotopic variations of the compounds of the present disclosure and embodiments thereof.
  • different isotopic forms of hydrogen (H) include protium ( 1 H) and deuterium ( 2 H, also denoted herein as D).
  • Protium is the predominant 25887 hydrogen isotope found in nature.
  • Enriching for deuterium may afford certain therapeutic advantages, such as increasing in vivo half-life or reducing dosage requirements or may provide a compound useful as a standard for characterization of biological samples.
  • Isotopically-enriched compounds can be prepared without undue experimentation by conventional techniques well known to those skilled in the art or by processes analogous to those described in the Schemes and Examples herein using appropriate isotopically-enriched reagents and/or intermediates.
  • salts refers to salts prepared from acceptable bases or acids including inorganic or organic bases and inorganic or organic acids.
  • Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc, and the like. Particular embodiments include the ammonium, calcium, magnesium, potassium, and sodium salts. Salts in the solid form may exist in more than one crystal structure, and may also be in the form of hydrates.
  • Salts derived from organic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N′-dibenzylethylene-diamine, diethylamine, 2- diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N- ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.
  • basic ion exchange resins such as arginine,
  • Particular embodiments include the citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, fumaric, and tartaric acids.
  • the disclosure also includes, in addition to the salt forms mentioned, inner salts or betaines (zwitterions). Salts can be obtained from the compounds of the present disclosure by customary methods which are known to the person skilled in the art, for example, by combination with an organic or inorganic acid or base in a solvent or dispersant, or by anion exchange or cation exchange from other salts.
  • the present disclosure also includes all salts of the compounds which, owing to low physiological compatibility, are not directly suitable 25887 for use in pharmaceuticals but which can be used, for example, as intermediates for chemical reactions or for the preparation of pharmaceutically acceptable salts.
  • the compounds of the present disclosure may exist in amorphous form and/or one or more crystalline forms, and as such all amorphous and crystalline forms and mixtures thereof of the compounds of the present disclosure, including the Examples, are intended to be included within the scope of the present disclosure.
  • some of the compounds of the present disclosure may form solvates with water (i.e., a hydrate) or common organic solvents such as but not limited to ethyl acetate or isobutyl alcohol, or solvents such as but not limited to hydrochloric acid or sulfuric acid.
  • solvates and hydrates, particularly the pharmaceutically acceptable solvates and hydrates, of the present compounds are likewise encompassed within the scope of this disclosure, along with unsolvated and anhydrous forms.
  • the term “substantially similar” used in reference to X-ray powder diffraction patterns means that the X-ray powder diffraction pattern of a polymorph may display “batch to batch” variations due to differences in the types of equipment used for the measurements, and fluctuations in both experimental conditions (e.g. purity and grain size of the sample) and instrumental settings (e.g. X-ray wavelengths; accuracy and sensitivity of the diffractometer; and “instrumental drift”) normally associated with the X-ray diffraction measurement. Due to these variations, the same polymorph may not contain X-ray powder diffraction peaks at exactly the same positions or intensities shown in the figures disclosed herein.
  • Example 2 Synthesis of 2-(4-(hydroxymethyl)phenyl)ethan-1-aminium chloride ((V)) C l NH 2 in 1-PrOH (500 mL) and water (10.0 mL) was added palladium on carbon (5% wt/wt, 54% water wet) (5.40 g, 1.37 mmol Pd), and triethylamine (7.40 mL, 53.1 mmol). The reactor was pressurized with 130 psi of hydrogen, warmed to 40 °C and vigorously agitated for 18 h. The reaction mixture was vented and filtered over CELITE®. The cake was washed with 1- PrOH/H 2 O (98:2, 300 mL).
  • a solution of HCl was prepared by slow addition of PivCl (128 g, 1.06 mol) to 1-PrOH (191 mL, 2.55 mol) at 0-20 °C. The resulting solution was aged at 0 °C for 1 h, then added slowly to the crude solution of EF-formamide ((IV)). The resulting solution was warmed to 50 °C and aged for 1 h. The batch was then seeded, aged at 50 °C for a further 13 h, then cooled to 40 °C, and MTBE (800 mL) was added over 2 h.
  • Example 3 Synthesis of (S)-2-((4-(hydroxymethyl)phenethyl)carbamoyl)-2- methylpyrrolidin-1-ium chloride ((VII)) O , g, 295 mmol) in NMP (150 mL) at 0 °C was added 1,1′-carbonyldiimidazole (CDI, 53.4 g, 329 mmol) portion-wise, maintaining the temperature below 10 °C. The reaction mixture was aged at 0 °C for 2 h before 2-propanol (6 mL) was added.
  • a solution of HCl was prepared in a separate vessel by slow addition of AcCl (46.8 mL) to 2-propanol (150 mL) at 0-20 °C.
  • the resulting HCl solution was aged at 20 °C for 1 h before being charged over 4 h to the main batch, which was then cooled to 0 °C.
  • the batch was then filtered, and the cake was washed with 2-propanol (3 x 200 mL) and dried under vacuum to provide (S)-2-((4- (hydroxymethyl)phenethyl)-carbamoyl)-2-methylpyrrolidin-1-ium chloride ((VII), 72.2 g, 97 wt%, 89% yield) as a crystalline white solid.
  • Example 4 Synthesis of hemi-sulfuric acid solvate-monohydrate of (S)-1-((S)-2-amino- 3-(4-methoxyphenyl)propanoyl)-N-(4-(hydroxymethyl)phenethyl)-2-methylpyrrolidine-2- carboxamide ((X)) 25887 acid ((VIII), 50.6 g, 171 mmol), (S)-2-((4-(hydroxymethyl)phenethyl)carbamoyl)-2-methylpyrrolidin- 1-ium chloride ((VII), 50 g, 155 mmol, 92.8 wt%), and 2-pyridinol 1-oxide (3.52 g, 31.0 mmol) in
  • the biphasic mixture was aged at 50 °C for 16 h before being cooled to 25 °C.
  • Tert-amyl alcohol (250 mL) and NaOH (10% aq, 200 mL) were charged, and the biphasic mixture was agitated for 3 h.
  • the layers were separated, and the organic layer was washed with Na2SO4 (10% aq, 150 mL).
  • the organics were concentrated to ⁇ 350 mL under vacuum at 50 °*C.
  • tert-amyl alcohol 300 mL was charged and the batch was concentrated to about 350 mL under vacuum at 50 °C, before being adjusted to 40 °C.
  • a solution of sulfuric acid (50 wt% aq, 10.9 mL, 78 mmol) in tert-amyl alcohol (150 mL) was prepared. Approximately 20% of the sulfuric acid solution was charged to the main batch over 1 h, which was then seeded and aged. The remaining sulfuric acid solution was 25887 charged over 8 h, followed by MTBE (275 mL) over 3 h.
  • Example 5 Synthesis of mono-hydrochloric acid hemi-2-butyl alcohol solvate of (S)-1- ((S)-2-amino-3-(4-methoxyphenyl)propanoyl)-N-(4-(hydroxymethyl)phenethyl)-2- methylpyrrolidine-2-carboxamide ((X)) Cl BocHN H H 2 N then added slowly to a crude solution of tert-butyl ((S)-1-((S)-2-((4- (hydroxymethyl)phenethyl)carbamoyl)-2-methylpyrrolidin-1-yl)-3-(4-methoxyphenyl)-1- oxopropan-2-yl)carbamate ((IX), 27.0 g, 50.8 mmol) in 2-BuOH (108 mL) at 45 °C.
  • reaction solution was aged at 45 °C then seeded with (X).
  • the resulting slurry was aged at 45 °C then cooled to 40 °C and MTBE (135 mL) was added dropwise over 3 h. The slurry was then cooled to room temperature before being filtered.
  • Tables 1-2 provide the major 2 ⁇ peaks and d-spacings for each of the crystalline forms of the compound of Formula (X).
  • Table 1 Diffraction peaks and corresponding d-spacings for crystalline form of the hemi-sulfuric acid salt of the compound of Formula (X).

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Abstract

Est divulgué un procédé de préparation de (S)-1-((S)-2-amino-3-(4-méthoxyphényl)propanoyl)-N-(4-(hydroxyméthyl)phénéthyl)-2-méthylpyrrolidine-2-carboxamide et de ses intermédiaires.
PCT/US2024/059924 2023-12-18 2024-12-13 Procédé de préparation de (s)-1-((s)-2-amino-3-(4-méthoxyphényl)propanoyl)-n-(4-(hydroxyméthyl)phénéthyl)-2-méthylpyrrolidine-2-carboxamide et de ses intermédiaires Pending WO2025136798A1 (fr)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030087833A1 (en) * 1999-10-05 2003-05-08 Kao Corporation Topical composition for skin
US20200354404A1 (en) * 2019-05-09 2020-11-12 The Feinstein Institutes For Medical Research Peptidomimetic agents, synthesis and uses thereof

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030087833A1 (en) * 1999-10-05 2003-05-08 Kao Corporation Topical composition for skin
US20200354404A1 (en) * 2019-05-09 2020-11-12 The Feinstein Institutes For Medical Research Peptidomimetic agents, synthesis and uses thereof

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
DATABASE PubChem 16 December 2005 (2005-12-16), Database accession no. 5311081 *

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